In vivo effects of anticonvulsant drugs on nerve terminal (synaptosomal) GABA levels in 11 brain regions of the rat

Summary Thein vivo effects of two GABA-elevating drugs with anticonvulsant properties, namely valproic acid (VPA) and aminooxyacetic acid (AOAA), on nerve terminal GABA levels in discrete rat brain regions were studied by means of a newly developed synaptosomal model. The profile of synaptosomal GABA increases obtained with AOAA was quite different from that seen with VPA. Thus, AOAA (30 mg/kg i.p., 2 hours) caused significant increases in olfactory bulb, cortex, hippocampus, thalamus and cerebellum, whereas VPA (200 mg/kg i.p., 0.5 hour) significantly increased GABA also in hypothalamus, substantia nigra and superior and inferior colliculus. In contrast to the regional selectivity of both drugs with respect to synaptosomal GABA levels, AOAA in most regions was more potent than VPA in increasing whole tissue GABA levels determined prior to subcellular fractionation. The data thus demonstrate that comparison of GABA levels in synaptosomal fractions rather than homogenates from discrete brain areas provides a more sensitive index of the action of GABA-elevating drugs administeredin vivo.     

Effect of phenoxybenzamine on the GABA system and on convulsive activity

The effect of phenoxybenzamine on the concentration of GABA and the aminooxyacetic acid (AOAA) induced accumulation of GABA in four brain regions was compared with its effect on the occurrence and latency of picrotoxin-induced convulsions. Also the effect of phenoxybenzamine on post-decapitation convulsions was followed. Whereas 0.1 mg/kg of phenoxybenzamine decreased the levels and the AOAA-induced accumulation of GABA in the substantia nigra and cerebellar cortex, 1.0 mg/kg produced an increased GABA accumulation in the substantia nigra. Both doses of the drug decreased the AOAA-induced accumulation of GABA in the cingulate cortex. Administration of phenoxybenzamine decreased the latency and increased or decreased the occurrence of picrotoxin-induced convulsions depending on the intensity of picrotoxin effect. Phenoxybenzamine also prolonged the latency and shortened the duration of post-decapitation convulsions in rats. The results suggest that two different mechanisms mediate the effects of phenoxybenzamine on the latency and occurrence of picrotoxin-induced convulsions.     

The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata

Levetiracetam ((S)-α-ethyl -2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently reported novel specific binding site for [³H]levetiracetam, unique to brain, may be involved. This binding site has not yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiracetam's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia nigra pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetiracetam, 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic acid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SNR activity may contribute to the anticonvulsant action of this drug.     

Anticonvulsant action of GABA receptor blockade in the nigrotectal target region

Anticonvulsant activity in a wide variety of experimental seizure models can be obtained by enhancing gamma-aminobutyric acid (GABA) transmission within the pars reticulata of substantia nigra. Recent evidence indicates that the nigrotectal projection may mediate some of the nigra-evoked anticonvulsant effects. The action of GABA within substantia nigra would, by inhibiting the GABAergic nigrotectal projections, cause disinhibition of target neurons in the superior colliculus. This hypothesis predicts that administration of GABA antagonists into the region of the superior colliculus that receives nigrotectal terminals should also have anticonvulsant actions. We therefore examined the effects of injections of bicuculline methiodide aimed at rostrolateral superior colliculus upon maximal electroshock convulsions. The incidence and duration of tonic hindlimb extension was substantially reduced by these injections, a result consistent with the hypothesis that the nigrotectal GABAergic pathway may mediate the anticonvulsant actions of GABA transmission in the substantia nigra.     

Lack of proconvulsant action of GABA depletion in substantia nigra in several seizure models.

The effect of intranigral application of a gamma-aminobutyric acid (GABA) synthesis inhibitor, was examined in 3 different rat seizure models. Bilateral intranigral infusion of isoniazid (150 micrograms) did not potentiate the effect of subcutaneous administration of a threshold dose (1.5 mg/kg) of the GABA antagonist bicuculline. Similarly, following pretreatment with intranigral isoniazid, neither severity nor latency to onset of seizures elicited by systemic injection of kainic acid (9 mg/kg) were modified. In addition, convulsive seizures evoked by the focal injection of bicuculline methiodide (40 ng) in an epileptogenic site within the deep prepiriform cortex (area tempestas) were not potentiated by intranigral isoniazid. These results were in sharp contrast to the marked potentiating effect of intranigral isoniazid (150 or 85 micrograms) on seizures induced by systemic administration of a subconvulsant dose of pilocarpine (150 mg/kg). In addition, we attempted to evoke a proconvulsant action from striatum. The striatum, origin of GABAergic projections to substantia nigra, is a region in which application of GABA antagonists have been found to be anticonvulsant in several seizure models. We therefore examined the effect of bilateral intrastriatal infusion of the GABA agonist, muscimol (5 ng) on the convulsant effect of threshold doses of systemically administered bicuculline (1.5 mg/kg). As was true with intranigral isoniazid, no proconvulsant effect was found using intrastriatal muscimol. Our data demonstrate that whereas striatonigral GABA circuitry can be activated by exogenous treatments so as to produce anticonvulsant actions in most seizure models, suppression of this circuitry does not potentiate convulsant activity in many of the same models.     

GABA turnover in mouse brain: Agreement between the rate of GABA accumulation after aminooxyacetic acid and the rate of disappearance after 3-mercaptopropionic acid

Summary GABA levels of the whole mouse brain were studied afterin vivo inhibition of GABA synthesis by 3-mercaptopropionic acid (3-MPA, 100mg/kg i.p.) and of GABA degradation by aminooxyacetic acid (AOAA, 3.8–60 mg/ kg i.v.). The influence of 3-MPA on GABA levels was investigated in brains where postmortal GABA accumulation was allowed to occur and in brains where this phenomenon was avoided by very rapid dissection and homogenization of the brain in acid (within 50 sec after decapitation). The postmortal GABA increase was blocked by 86% after injection of 3-MPA 3 min before decapitation. In the group where the postmortal accumulation was avoided by very rapid homogenization of the brain in acid, GABA levels decreased by 15 % within 2 min after 3-MPA (mean turnover time=14 min). From 2 to 4 min the GABA concentration remained stable at this decreased level. GABA accumulation after AOAA was maximal after a dose of 7.5 to 15 mg/kg. i.v. Doses higher than 60mg/kg always produced convulsions. The phase of most rapid accumulation of GABA after AOAA indicates a mean turnover time of about 10 min. The first rapid phase of accumulation was followed by a slower phase. It is probable that the turnover time of whole mouse brain GABA is approximately 10–14 min. It is also concluded that AOAA in a dose of around 15 mg/kg i.v. hardly can inhibit GADin vivo in the mouse brain and that this dose, by this route of administration, could be used for studies of GABA synthesisin vivo in the mouse.     

Elevation of brain GABA concentrations with amino-oxyacetic acid; effect on the hyperactivity syndrome produced by increased 5-hydroxytryptamine synthesis in rats

Summary Pretreatment of rats with aminooxyacetic acid (AOAA; 40 mg/kg) raised the concentration of rat brain GABA and inhibited the hyperactivity produced by increasing brain 5-hydroxytryptamine (5-HT) concentration by administration of tranylcypromine and L-tryptophan. The maximum effect was seen 90 min after AOAA injection with smaller effects 30 and 180 min after injection. AOAA did not affect the rate of 5-HT accumulation in the brain, but did inhibit the hyperactivity response which follows injection of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine, suggesting that post-synaptic 5-HT responses were being inhibited.AOAA also inhibited the locomotor activity which follows administration of tranylcypromine and L-dopa. Blockade of GABA receptors by injection of picrotoxin (2.5 mg/kg) enhanced the dopamine hyperactivity. Since a dopaminergic system has been shown to be involved in the 5-HT hyperactivity syndrome and appears to act post-synaptically to the 5-HT neurones initiating the syndrome it is suggested that inhibition of the 5-HT hyperactivity syndrome may be due to accumulation of GABA distal to the dopaminergic receptors.     

Substantia nigra is an anticonvulsant site of action of topiramate in the focal pilocarpine model of limbic seizures

PURPOSE: The substantia nigra pars reticulata (SNR) is known to play a role in gating and control of seizures. Prompted by the observation that intrahippocampal topiramate (TPM) administration does not suppress limbic seizures in the focal pilocarpine model, we investigated the role of the SNR in the anticonvulsant mechanism of action of TPM. METHODS: Limbic seizures were evoked in freely moving rats by intrahippocampal administration of pilocarpine via a microdialysis probe. Changes in hippocampal extracellular (EC) glutamate and GABA concentrations were monitored. Effects of intraperitoneal (10-200 mg/kg), intrahippocampal (1-5 mM), and bilateral intranigral (100-300 nmol) TPM administration on pilocarpine-induced seizures and neurochemical changes were evaluated. Effects of TPM administration alone on hippocampal and nigral EC amino acid concentrations were also studied. RESULTS: Systemic and intranigral, but not intrahippocampal TPM administration suppressed pilocarpine-induced seizures and neurochemical changes. Nigral GABA(A) receptor blockade by picrotoxin abolished the anticonvulsant effect of TPM in SNR. Systemic TPM administration increased hippocampal glutamate and decreased GABA. Intranigral TPM administration increased hippocampal glutamate, but not GABA. Intrahippocampal TPM increased hippocampal glutamate and GABA, but only at high concentrations. CONCLUSIONS: In the focal pilocarpine model, TPM does not exert its anticonvulsant effect at the site of seizure initiation. We identified the SNR as a site of action of TPM, and showed that the nigral GABA-ergic system is central to TPM's anticonvulsant effect in SNR. Anticonvulsant effects and neurochemical changes in hippocampus following intranigral TPM administration suggest the existence of a nigro-hippocampal circuit, which may be involved in the control of limbic seizures.     

Acute effects of N-(2-propylpentanoyl)urea on hippocampal amino acid neurotransmitters in pilocarpine-induced seizure in rats

The present study aimed to investigate the anticonvulsant activity as well as the effects on the level of hippocampal amino acid neurotransmitters (glutamate, aspartate, glycine and GABA) of N-(2-propylpentanoyl)urea (VPU) in comparison to its parent compound, valproic acid (VPA). VPU was more potent than VPA, exhibiting the median effective dose (ED₅₀) of 49 mg/kg in protecting rats against pilocarpine-induced seizure whereas the corresponding value for VPA was 322 mg/kg. In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate whereas no significant change was observed on the level of glycine and GABA. Pretreatment with either VPU (50 and 100 mg/kg) or VPA (300 and 600 mg/kg) completely abolished pilocarpine-evoked increases in extracellular glutamate and aspartate. In addition, a statistically significant reduction was also observed on the level of GABA and glycine but less than a drastic reduction of glutamate and aspartate level. Based on the finding that VPU and VPA could protect the animals against pilocarpine-induced seizure it is suggested that the reduction of inhibitory amino acid neurotransmitters was comparatively minor and offset by a pronounced reduction of glutamate and aspartate. Therefore, like VPA, the finding that VPU could drastically reduce pilocarpine-induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine-induced seizure in experimental animals. Some other mechanism than those being reported herein should be further investigated.     

Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum

Bicuculline methiodide (BMI), a gamma-aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles, amygdala, hippocampus, thalamus, neocortex, and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mg/kg, i.p.), with an ED50 of 94 fmol (range 45-195 fmol). No topographical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA-mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA-mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocarpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.     

The effect of sodium valproate on extracellular GABA and other amino acids in the rat ventral hippocampus: an in vivo microdialysis study

We report the effects of i.p. administration of sodium valproate (VPA) on extracellular concentrations of various amino acids in the rat ventral hippocampus studied using in vivo microdialysis, followed by HPLC with fluorometric detection. At the doses used (100, 200 and 400 mg/kg), VPA had no effect on extracellular aspartate, glutamine and taurine, whilst inducing a small, but not statistically significant increase in glutamate at 200 and 400 mg/kg. In contrast, VPA administration produced a biphasic effect on extracellular GABA levels which was dependent on the dose used. At 100 mg/kg, VPA reduced GABA concentrations by 50% when compared to basal. 200 mg/kg VPA had virtually no effect, whilst 400 mg/kg VPA raised extracellular GABA levels to 200% of basal. The results are discussed in relation to the known pharmacological and anticonvulsant actions of VPA.     

Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats

Nondopaminergic, presumably GABAergic neurons in the substantia nigra pars reticulata (SNR) are thought to function as a gating mechanism for seizure propagation. Systemic administration of anticonvulsant doses of the antiepileptic drug valproate (VPA) has previously been reported to inhibit the firing of nondopaminergic SNR neurons in anesthetized but not in awake, paralyzed and locally anesthetized rats, suggesting that the findings in anesthetized rats were due to an interaction between VPA and the general anesthetic used. In the present study, we determined the influence of different anesthetic measures on the effect of an anticonvulsant dose of VPA (100 mg/kg) on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in rats. Rats were anesthetized by continuous infusion of the general anesthetic chloral hydrate, the dissociative anesthetic ketamine or the narcotic opioid fentanyl, or were only locally anesthetized and paralyzed. VPA significantly reduced SNR firing in all groups with a time course that matched its anticonvulsant time course in rodents. However, VPA's inhibitory effect on SNR firing was significantly less marked under anesthesia with chloral hydrate than in any of the other groups, indicating that this anesthetic suppresses the action of VPA, which may be related to an interaction with GABA-related processes in the SNR. The closest approximation to the effect of VPA in awake rats was obtained under anesthesia with ketamine, while VPA's inhibitory action on SNR neuronal firing seemed to be enhanced in the fentanyl group, which exhibited the highest baseline firing rates of all groups. Determination of VPA in the SN showed that the difference in VPA's inhibitory effect on SNR neurons was not secondary to differences in local drug concentrations. The data demonstrate that VPA is capable of significantly slowing the spontaneous activity of nondopaminergic SNR neurons, but that the magnitude of this effect depends on the anesthetic measures used. In view of the presumed role of SNR neurons in seizure propagation and the finding that VPA consistently inhibits these neurons at an anticonvulsant dose, the present data suggest that suppression of spontaneous SNR neuronal firing may be an important mechanism through which VPA exerts its anticonvulsant properties.     

Effects of valproic acid in cultured mammalian neurons

Valproic acid (VPA) has been postulated to exert its anticonvulsant effects by interaction with the postsynaptic GABA receptor. To test that hypothesis, we applied VPA in clinically appropriate concentrations to cortical neurons in dissociated cell culture. VPA did not enhance the postsynaptic effect of GABA, but did decrease the generation of sodium-dependent action potentials. VPA may exert anticonvulsant effects by inhibiting spike generation, independent of the GABAergic system.     

Effect of morphine on dynorphin B and GABA release in the basal ganglia of rats

In vivo microdialysis was used to study the effects of systemic, as well as intracerebral administration of morphine and naloxone on dynorphin B release in neostriatum and substantia nigra of rats. The release of dopamine (DA), γ-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) was also investigated. Systemic injection of morphine (1 mg/kg s.c.) induced long-lasting increases in extracellular dynorphin B and GABA levels in the substantia nigra, whereas DA, Glu and Asp levels, measured in the same region, were not significantly affected. No effect on striatal neurotransmitter levels was observed following systemic morphine administration. Local perfusion of the substantia nigra with morphine (100 μM) through the microdialysis probe also increased nigral dynorphin B and GABA levels. Perfusion of the neostriatum with morphine (100 μM) significantly increased GABA and dynorphin B levels in the ipsilateral substantia nigra, but no effect was observed locally. Naloxone blocked the effect of systemic morphine administration on nigral dynorphin B and GABA release, already at a dose of 0.2 mg/kg s.c. Naloxone alone, given either systemically (0.2–4 mg/kg s.c.) or intracerebrally (1–100 μM), did not affect dynorphin B or amino acid levels, either in neostriatum or in substantia nigra. However, naloxone produced a concentration-dependent increase in DA levels. The present results indicate that systemic morphine administration stimulates the release of dynorphin B in the substantia nigra, probably by activating the μ-subtype of opioid receptor, since the effect of morphine on nigral dynorphin B and GABA was antagonized by a low dose of naloxone. The increase in extracellular DA levels produced by high concentrations of naloxone, both in neostriatum and substantia nigra, indicates a disinhibitory effect of this drug on DA release, probably via a non-μ subtype of opioid receptors located on nigro-striatal DA neurones.     

Increase in antiepileptic efficacy during prolonged treatment with valproic acid: role of inhibition of histone deacetylases?

Valproic acid (VPA) is a major antiepileptic drug (AED) with efficacy against multiple seizure types. It has a rapid onset of action but its anticonvulsant activity increases during prolonged treatment, which cannot be explained by drug or metabolite accumulation in plasma or brain. Among numerous other effects on diverse drug targets, VPA is an inhibitor of histone deacetylases (HDACs) that are involved in modulation of gene expression. The functional consequences of HDAC inhibition typically develop slowly during treatment with HDAC inhibitors such as VPA. We therefore hypothesized that inhibition of brain HDACs by VPA and resultant increases in gene expression could explain the increase in anticonvulsant activity during prolonged treatment with this drug. This hypothesis was tested by comparing the effects of VPA and the selective HDAC inhibitor, trichostatin A (TSA), in a mouse model of generalized seizures. Intravenous infusion of pentylenetetrazole (PTZ) was used to determine the effects of the drugs on different seizure types, i.e., myoclonic, clonic and tonic seizures. VPA (200mg/kg b.i.d.) rapidly increased PTZ thresholds to all seizure types, but this effect increased up to threefold during prolonged treatment. Following low (0.5mg/kg b.i.d.) or high (5mg/kg b.i.d.) dose treatment with TSA, no dose-dependent anticonvulsant effects were determined. This finding argues against a role of HDAC inhibition for the anticonvulsant activity of VPA. In view of the multiple extra- and intracellular targets of VPA, the experimental strategy used in the present study may be helpful to assess which specific molecular effects of VPA are relevant for the antiepileptic activity of this drug, and which are not.     

Valproate Effect on γ-Aminobutyric Acid Release in Pars Reticulata of Substantia Nigra: Combination of Push-pull Perfusion and Fluorescence Histochemistry

Summary: To study further the previously demonstrated suppressive in vivo effect of sodium valproate (VPA) on y-aminobutyric acid (GABA) release in the preoptic area, we examined GABA neurotransmission in substantia nigra (SN), using the push-pull cannula technique in freely moving ovariectomized rats. To clarify whether the area in the substantia nigra that is actually perfused is pars reticulata, known to receive rich GABAergic input from striatum, we used the retrograde fluorescence tracer fast blue (FB) after each perfusion experiment, applying the tracer through the push-pull cannula. Nigral perfusion with VPA caused significant suppression of local GABA release. This effect was more marked in a subgroup of animals showing retrograde labeled cell bodies in striatum, i.e., animals with a tracer application site and therefore also a perfusion site precisely in pars reticulata. Our data suggest that VPA inhibits GABA release in rat SN as it does in the preoptic area, which may be in agreement with our hypothesis of enhanced GABAergic neurotransmission by VPA, causing suppression of presynaptic GABA release through negative feedback actions on the GABA autoreceptor complex. Furthermore, the combination of push-pull cannula technique and retrograde fluorescence tracer application appears to be an important tool to prove afferent connections of the area actually perfused in neuronal networks.     

Dopamine control of seizure propagation: intranigral dopamine D1 agonist SKF-38393 enhances susceptibility to seizures

The involvement of dopamine (DA) in human and experimental epilepsy has been discounted as DAergic drugs have little effect on convulsions. This work presents evidence that bilateral microinjection of the DAD1 agonist SKF-38393 into the substantia nigra enhances the susceptibility of rats to seizures, with an ED50 of 20 pmol (range 13-31 pmol), converting subconvulsant doses of the cholinergic agonist pilocarpine (200 mg/kg; i.p.) into convulsant ones. The proconvulsant action of SKF-38393 was reversed by blocking D1-mediated transmission in the substantia nigra with the D1 antagonist SCH-23390. The D2 agonist LY-171555 did not modulate the threshold for limbic seizures when injected into the substantia nigra. In the striatum, the D2 agonist LY-171555 protected rats against limbic seizures induced by systemic administration of pilocarpine (380 mg/kg; i.p.), with an ED50 of 2 pmol (range 1.4-2.8 pmol). The anticonvulsant action of LY-171555 in the striatum was reversed by haloperidol. The D1 agonist SKF-38393 did not affect pilocarpine seizures following administration into the striatum. Systemic administration of DAergic drugs showed that the D1 agonist SKF-38393 decreased the threshold for pilocarpine seizures, with an ED50 of 0.81 mg/kg (range 0.45-1.47 mg/kg), whereas the D2 agonist LY-171555 had no effect on susceptibility of rats to pilocarpine. The proconvulsant action of SKF-38393 was blocked by the D1 antagonist SCH-23390. These results suggest that DA differentially modulates seizure threshold in the forebrain acting via D1 mechanisms in the substantia nigra and D2 mechanisms in the striatum.     

Anticonvulsant effect of intranigral fluoxetine

Bilateral focal injections of the serotonin uptake inhibitor, fluoxetine (1.75–7.0 nmol) into substantia nigra (SN) protected against convulsive seizures evoked by the focal injection of bicuculline methiodide into area tempestas, an epileptogenic site within the deep prepiriform cortex. Injection of fluoxetine unilaterally in SN or bilaterally into a site dorsal to SN was not anticonvulsant. Blockade of nigral γ-aminobutyric acid (GABA) receptors with bicuculline in SN did not reverse the anticonvulsant action of intranigral fluoxetine. These data suggest that serotonergic transmission in SN exerts a seizure suppressing action which is independent of GABA transmission in SN.     

GABA and dopamine interaction in the basal ganglia: dopaminergic supersensitivity following chronic elevation of brain γ-aminobutyric acid levels

The influence of chronic activation of the gamma-aminobutyric acid (GABA) system on dopaminergic function was evaluated in male rats. Activation of the GABA system was achieved by raising the brain concentration of GABA with aminooxyacetic acid (AOAA), a GABA-transaminase (GABA-T) inhibitor. Repeated i.p. injection (40 or 80 mg/kg/day for 8 days) of AOAA produced a sustained elevation of GABA concentration in the striatum. Beginning 26 h following the last dose of a regimen of AOAA treatment (80 mg/kg/day for 8 days), the animals exhibited a characteristic spontaneous 'sham-fighting' behavioral stereotypy which peaked at 34 h after the last dose of AOAA; this spontaneous behavior dissipated by 38 h postdose. When challenged with apomorphine, the sham-fighting behavior was interspersed with intense fighting episodes; these precipitated behaviors were evident for up to 2 weeks posttreatment observation period. Animals given a lower dose of AOAA (40 mg/kg/day X 8) did not show signs of spontaneous sham-fighting, but responded with fighting upon apomorphine challenge. Qualitatively similar behavioral effects were obtained when gamma-acetylenic GABA (30 mg/kg/day, i.p. for 8 days) was used as the inhibitor of GABA-T. Measurement of dopamine and its acid metabolites in the striatum showed an enhanced turnover of dopamine during the spontaneous behavioral response, suggesting a rebound phenomenon. The levels of 5-hydroxytryptamine or its acid metabolite or neuroactive amino acids such as glutamate, aspartate, taurine, glycine, glutamine in the striatum were not altered by any of the treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory influence of GABA on central serotonergic transmission. Raphé nuclei as the neuroanatomical site of the GABAergic inhibition of cerebral serotonergic neurons

Acute injection of the gamma-aminobutyric acid (GABA) mimetics progabide, aminooxyacetic acid, gamma-acetylenic GABA and dipropylacetamide reduced 5-hydroxytryptophan (5-HTP) accumulation in serotonergic nerve terminal regions (prefrontal cortex, olfactory tubercle, septum, striatum, hypothalamus, hippocampus, substantia nigra, cerebellum and spinal cord) as well as in corresponding cell body areas (raphé dorsalis, medianus, pontis and magnus). This effect was antagonized by bicuculline. The inhibition of serotonin (5-HT) synthesis induced by a single progabide administration was accentuated on repeated treatment in the striatum, prefrontal cortex and cerebellum but was similar to that seen after acute treatment in the other areas. Local infusion of high concentrations of GABA or GABA mimetics into the striatum, septum or substantia nigra failed to modify 5-HTP accumulation in these areas. Cerebral hemitransection antagonized the ability of progabide (1200 mg/kg i.p.) to diminish 5-HTP accumulation in the striatum, hippocampus and prefrontal cortex. Intra-raphé dorsalis infusion of muscimol (0.1-100 ng) or GABA (1-100 micrograms) decreased 5-HT synthesis in the corresponding projection areas (e.g. striatum, substantia nigra, cortex) but not in the hippocampus or cerebellum. Conversely, intra-raphé medianus infusion of these drugs diminished 5-HTP accumulation in the corresponding projection areas (e.g. hippocampus, septum, cortex) but not in the striatum or cerebellum. Intra-raphé dorsalis or medianus injection of GABA antagonists (bicuculline, picrotoxinin, RU-5135) was without effect on cerebral 5-HT synthesis but antagonized the diminution of the amine synthesis observed in corresponding projection areas after intra-raphé dorsalis or medianus infusion of muscimol or GABA. These results suggest that GABA exerts an inhibitory (non-tonic) control over central serotonergic neurons which is mediated via GABA receptors located in the raphé nuclei.